Design, synthesis, cytoselective toxicity, structure-activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells

Ten cytoselective compounds have been identified from 372 thiazolidinone analogues. by applying iterative library approaches. These compounds selectively killed both non-small cell lung cancer cell line H460 and its paclitaxel-resistant variant H460(taxR) at an IC50 between 0.21 and 2.93 mu M while showing much less toxicity to normal human fibroblasts at concentrations up to 195 mu M. Structure-activity relationship studies revealed that (1) the nitrogen atom on the 4-thiazolidinone ring (ring Bin Figure 1) cannot be substituted, (2) several substitutions on ring A are tolerated at various positions, and (3) the substitution on ring C is restricted to the - NMe2 group at the 4-position. A pharmacophore derived from active molecules suggested that two hydrogen bond acceptors and three hydrophobic regions were common features. Activities against P-gp-overexpressing and paclitaxel-resistant cell line H460(taxR) and modeling using a previously validated P-gp substrate pharmacophore suggested that active compounds were not likely P-gp substrates.